DESCRIPTION Abstract: I. Pioneer a new approach for drug target discovery that has implications for a broad range of developmental and chronic illnesses. II. Develop a robust technology platform for large-scale targeted genomic engineering to enable more complete recapitulation of human disease genotypes in animal models. We will enable precise introduction of combinations of disease-associated genetic mutations into a single animal model. III. Develop a technology for targeted epigenome modification to enable direct functional testing of causal links between specific epigenetic modifications and disease pathophysiology. IV. Identify fundamentally new classes of therapeutics for major depression. PUBLIC HEALTH RELEVANCE Major depressive disorder is a devastating mental illness affecting millions of Americans annually, with a large fraction of patients unresponsive to available therapies. The proposed project aims to identify fundamentally new classes of therapeutics by probing the epigenetic mechanisms contributing to major depression, through a combination of innovative technology development, and systematically establishing causal links between epigenetic targets and disease phenotype. The technologies developed through this proposal will establish a new epigenetic paradigm for drug discovery and have broad impacts for many fields of biomedical research including cancer, diabetes, obesity, and other neurological disorders. THE FOLLOWING RESUME SECTIONS WERE PREPARED BY THE SCIENTIFIC REVIEW OFFICER TO SUMMARIZE THE OUTCOME OF DISCUSSIONS OF THE REVIEW COMMITTEE ON THE FOLLOWING ISSUES. COMMITTEE BUDGET RECOMMENDATIONS: The budget was recommended as requested.